Formulations and methods for treatment of inflammatory skin diseases

ABSTRACT

Topically administrable compositions and methods are included for treating inflammatory skin disease in mammals. The composition includes a therapeutic amount of antihistamine selected from the group consisting of a non-sedating antihistamine, a physiologically acceptable acid of a non-sedating antihistamine, a salt of a non-sedating antihistamine, an amide of a non-sedating antihistamine, and a combination of two or more of these, and emu oil product selected from the group consisting of emu oil, a biologically active fraction of emu oil, and a combination of these. The composition further includes a therapeutic amount of topical corticosteroid. The combination of non-sedating antihistamine and corticosteroid with emu oil has been found to produce a synergistic effect that is more effective in the treatment of inflammatory skin disease than the compounds used separately.

PRIORITY

The present application is a U.S. National Phase of International PCTApplication No. PCT/US13/32726 filed on Mar. 17, 2013, and is alsorelated to, and claims the priority benefit of, U.S. Provisional PatentApplication Ser. Nos. 61/624,725, filed Apr. 16, 2012, and 61/725,761,filed Nov. 13, 2012, each of which is hereby incorporated by referencein their entirety into this disclosure.

BACKGROUND

The emu (Dromiceius novae-hollandiae) is the second largest member ofthe group of flightless birds and is indigenous to Australia. Emus canbe raised like ordinary farm animals and used for their valuableproducts, which include very low fat meat, supple leather hides,decorative and nutritional eggs, and rich oil. Emu oil may be extractedor rendered from the body fat of the emu and is known to containtriglyceride esters of long-chain saturated and unsaturated fatty acids,including oleic acid, linoleic acid, palmitic acid, and stearic acid.

Atopic dermatitis and other forms of eczema are inflammatory, pruritic(i.e., itchy) skin diseases that affect between 10 and 20 percent of theUnited States (U.S.) population, causing considerable morbidity, poorquality of life, and high medical costs for both the patient andsociety. Topically administered glucocorticoids are a main form oftherapy; however, prolonged use of topical glucocorticoids is associatedwith skin thinning, permanent stretch marks, dermal atrophy, reboundeffects, tachyphylaxis, and potential systemic absorption, which cancause numerous systemic side effects. Topical calcineurin inhibitors(e.g., Elidel® and Protopic® creams and ointments) are effective but areinfrequently used as a result of FDA-required “black box” warningsconcerning a potential increase in systemic malignancies in patientsusing these topical preparations.

Psoriasis is also a chronic pruritic inflammatory skin disease affecting2% of the U.S. population. Inflammation and tumor necrosis factor-alpha(“TNF-alpha”) are of crucial importance in the pathogenesis of psoriasisand its treatment. Based on the severity of the disease presentation,topical glucocorticoids and vitamin D analogs, either by themselves orin combination with phototherapy or systemic agents (such asmethotrexate, cyclosporine A, Humira®, Stelara®, Soriatane®, etc.), havebeen used for therapy. However, these agents can be extremely expensive,costing more than $20,000 per year per patient.

Histamine is a compound involved in local immune responses of humans andother animals. As part of an immune response to foreign pathogens,histamine is produced by basophils and mast cells found in nearbyconnective tissues. Upon release from these cells, histamines produceincreased vascular permeability, causing fluid to escape fromcapillaries into tissues, which can lead to inflammation and itchiness,among other responses. Histamine triggers an immune system response bycombining with specific cellular histamine receptors. The four histaminereceptors that have been discovered in humans and animals are designatedH₁ through H₄. Compounds, known as antihistamines, have been developedthat do not prevent the release of histamine but instead inhibit theaction of histamine by blocking it from attaching to the histaminereceptors. Most commonly used antihistamines inhibit action specificallyat the H₁ receptor and are referred to as H₁ antihistamines. While someH₁ antihistamines have sedative side effects, so-called “secondgeneration” or “non-sedating” antihistamines do not cross theblood-brain barrier and, thus, do not cause drowsiness. Further, not allH₁ antihistamines inhibit the inflammatory response that results fromthe release of histamine in humans.

Extensive investments of time and capital are required to obtain FederalDrug Administration (FDA) approval to sell and market a new drug. Thecost of approval is one reason that only three topical dermatologicaldrugs were approved by the FDA in the last five years. Instead,pharmaceutical companies are primarily directing their efforts todevelop and patent new delivery systems and formulations to moreefficiently carry active ingredients (i.e., drugs) through the stratumcorneum skin barrier. These new formulations include solid lipidnanoparticles, liposomes and niosomes, transferosomes, ethosomes,cyclodextrins, and sol-gel microcapsules.

Accordingly, there is a need for an anti-inflammatory, antipruritic,moisturizing topical formulation for treating atopic dermatitis,psoriasis, and other inflammatory diseases of the skin without the sideeffects of chronic topical steroid use.

BRIEF SUMMARY

According to one aspect of the present invention, a composition for thetreatment of inflammatory skin diseases is disclosed. In at least oneembodiment, a topically administrable composition for treatinginflammatory skin disease in mammals includes a therapeutic amount ofantihistamine selected from the group consisting of a non-sedatingantihistamine, a physiologically acceptable acid of a non-sedatingantihistamine, a salt of a non-sedating antihistamine, an amide of anon-sedating antihistamine, and a combination of two or more thereof,and emu oil product selected from the group consisting of emu oil, abiologically active fraction of emu oil, and a combination thereof.

In at least one embodiment, the non-sedating antihistamine is selectedfrom the group consisting of cetirizine, levocetirizine, loratadine,fexofenadine, rupatadine, acrivastine, ebastine, bilastine, and acombination of two or more thereof. The physiologically acceptable acidof the non-sedating antihistamine is selected from the group consistingof an acid of cetirizine, an acid of levocetirizine, an acid ofloratadine, an acid of fexofenadine, an acid of rupatadine, an acid ofacrivastine, an acid of ebastine, an acid of bilastine, and acombination of two or more thereof. The non-sedating antihistamine isselected from the group consisting of a salt of cetirizine, a salt oflevocetirizine, a salt of loratadine, a salt of fexofenadine, a salt ofrupatadine, a salt of acrivastine, a salt of ebastine, a salt ofbilastine, and a combination of two or more thereof. The amide of anon-sedating antihistamine is selected from the group consisting of anamide of cetirizine, an amide of levocetirizine, an amide of loratadine,an amide of fexofenadine, an amide of rupatadine, an amide ofacrivastine, an amide of ebastine, an amide of bilastine, and acombination of two or more thereof.

In at least one embodiment, the composition includes 0.1 to 5.0 wt.-% ofthe antihistamine and at least 75 wt.-% of the emu oil product. In atleast one embodiment, the composition includes 2.0 wt.-% of theantihistamine, and at least 85 wt.-% of the emu oil product.

In at least one embodiment, the composition includes a therapeuticamount of topical corticosteroid. The topical corticosteroid is selectedfrom the group consisting of desoximetasone, fluocinonide, halcinonide,amcinonide, hydrocortisone, and a combination of two or more thereof. Inat least one embodiment, the composition includes 0.1 to 3.0 wt.-% ofthe topical corticosteroid, 0.1 to 5.0 wt.-% of the antihistamine, andat least 75 wt.-% of the emu oil product. In at least one embodiment thecomposition includes 0.25 wt.-% of the topical corticosteroid, 2.0 wt.-%of the antihistamine, and at least 85 wt.-% of the emu oil product. Inat least one embodiment, the composition includes 1.0 wt.-% of thetopical corticosteroid, 2.0 wt.-% of the antihistamine, and at least 85wt.-% of the emu oil product.

In at least one embodiment, the composition further includes apreservative, and a neutral emulsifying agent. In at least oneembodiment, the composition includes 0.1 to 1.0 wt.-% of preservative.In at least one embodiment, the composition includes 0.2 wt.-% ofpreservative. In at least one embodiment, the preservative includesmethylparaben and the emulsifying agent includes propylene glycol.

In at least one embodiment, the antihistamine is selected from the groupconsisting of cetirizine, a physiologically acceptable acid ofcetirizine, a salt of cetirizine, an amide of cetirizine, and acombination of two or more thereof. In at least one embodiment, theantihistamine is selected from the group consisting of levocetirizine, aphysiologically acceptable acid of levocetirizine, a salt oflevocetirizine, an amide of levocetirizine, and a combination of two ormore thereof. In at least one embodiment, the composition includesantihistamine selected from the group consisting of cetirizine, aphysiologically acceptable acid of cetirizine, a salt of cetirizine, anamide of cetirizine, and a combination of two or more thereof, and thetopical corticosteroid is desoximetasone. In at least one embodiment,the composition includes antihistamine selected from the groupconsisting of levocetirizine, a physiologically acceptable acid oflevocetirizine, a salt of levocetirizine, an amide of levocetirizine,and a combination of two or more thereof, and the topical corticosteroidis desoximetasone. In at least one embodiment, the composition includesantihistamine selected from the group consisting of cetirizine, aphysiologically acceptable acid of cetirizine, a salt of cetirizine, anamide of cetirizine, and a combination of two or more thereof, and thetopical corticosteroid is hydrocortisone. In at least one embodiment,the composition includes antihistamine selected from the groupconsisting of levocetirizine, a physiologically acceptable acid oflevocetirizine, a salt of levocetirizine, an amide of levocetirizine,and a combination of two or more thereof, and the topical corticosteroidis hydrocortisone.

According to one aspect of the present invention, a method of treatinginflammatory skin disease in mammals is disclosed. The method includestopically applying to the skin of a mammal a topically administrablecomposition including a therapeutic amount of antihistamine selectedfrom the group consisting of a non-sedating antihistamine, aphysiologically acceptable acid of a non-sedating antihistamine, a saltof a non-sedating antihistamine, an amide of a non-sedatingantihistamine, and a combination of two or more thereof, and emu oilproduct selected from the group consisting of emu oil, a biologicallyactive fraction of emu oil, and a combination thereof. The methodfurther includes repeating the topical application of the composition asindicated for resolution or control of the skin disease. In at least oneembodiment, the method includes applying a composition further includinga topical corticosteroid.

According to one aspect of the present invention, a kit for treatinginflammatory skin disease in mammals is disclosed. The kit includes afirst composition, where the first composition includes a therapeuticamount of a first antihistamine selected from the group consisting of afirst non-sedating antihistamine, a first physiologically acceptableacid of a non-sedating antihistamine, a first salt of a non-sedatingantihistamine, a first amide of a non-sedating antihistamine, and acombination of two or more thereof, and a first emu oil product selectedfrom the group consisting of emu oil, a biologically active fraction ofemu oil, and a combination thereof. The kit further includes a secondcomposition, where the second composition includes a therapeutic amountof a second antihistamine selected from the group consisting of a secondnon-sedating antihistamine, a second physiologically acceptable acid ofa non-sedating antihistamine, a second salt of a non-sedatingantihistamine, a second amide of a non-sedating antihistamine, and acombination of two or more thereof; a therapeutic amount of topicalcorticosteroid; and a second emu oil product selected from the groupconsisting of emu oil, a biologically active fraction of emu oil, and acombination thereof.

In at least one embodiment, a method of treating inflammatory skindisease in mammals includes topically applying to the skin of a mammal atopically administrable first composition that includes a therapeuticamount of a first antihistamine selected from the group consisting of afirst non-sedating antihistamine, a first physiologically acceptableacid of a non-sedating antihistamine, a first salt of a non-sedatingantihistamine, a first amide of a non-sedating antihistamine, and acombination of two or more thereof a therapeutic amount of topicalcorticosteroid; and a first emu oil product selected from the groupconsisting of emu oil, a biologically active fraction of emu oil, and acombination thereof. The method further includes repeating the topicalapplication of the first composition as indicated for resolution orcontrol of the skin disease. The method further includes topicallyapplying a topically administrable second composition that includes atherapeutic amount of a second antihistamine selected from the groupconsisting of a second non-sedating antihistamine, a secondphysiologically acceptable acid of a non-sedating antihistamine, asecond salt of a non-sedating antihistamine, a second amide of anon-sedating antihistamine, and a combination of two or more thereof;and a second emu oil product selected from the group consisting of emuoil, a biologically active fraction of emu oil, and a combinationthereof. The method further includes repeating the topical applicationof the second composition as indicated for one or more benefits, suchbenefits selected from the group consisting of control of the skindisease, prevention of recurrence of the skin disease, and avoiding sideeffects of the first composition. The method further includes topicallyapplying the first composition as indicated to control recurrence of theskin disease.

In at least one embodiment, the first non-sedating antihistamine and thesecond non-sedating antihistamine are selected from the group consistingof cetirizine, levocetirizine, loratadine, fexofenadine, rupatadine,acrivastine, ebastine, bilastine, and a combination of two or morethereof. In at least one embodiment, the first acid of the non-sedatingantihistamine and the second acid of the non-sedating antihistamine areselected from the group consisting of an acid of cetirizine, an acid oflevocetirizine, an acid of loratadine, an acid of fexofenadine, an acidof rupatadine, an acid of acrivastine, an acid of ebastine, an acid ofbilastine, and a combination of two or more thereof. In at least oneembodiment, the first salt of the non-sedating antihistamine and thesecond salt of the non-sedating antihistamine are selected from thegroup consisting of a salt of cetirizine, a salt of levocetirizine, asalt of loratadine, a salt of fexofenadine, a salt of rupatadine, a saltof acrivastine, a salt of ebastine, a salt of bilastine, and acombination of two or more thereof. In at least one embodiment, thefirst amide of a non-sedating antihistamine and the second amide of anon-sedating antihistamine are selected from the group consisting of anamide of cetirizine, an amide of levocetirizine, an amide of loratadine,an amide of fexofenadine, an amide of rupatadine, an amide ofacrivastine, an amide of ebastine, an amide of bilastine, and acombination of two or more thereof. In at least one embodiment, thefirst antihistamine and the second antihistamine are the sameantihistamine.

In at least one embodiment, the first composition and the secondcomposition each include 0.1 to 5.0 wt.-% of antihistamine and at least75 wt.-% of the emu oil product. In at least one embodiment, the firstcomposition and the second composition each include 2.0 wt.-% ofantihistamine and at least 85 wt.-% of the emu oil product. In at leastone embodiment, the first composition includes 0.1 to 3.0 wt.-% of thetopical corticosteroid. In at least one embodiment, the firstcomposition includes 0.25 wt.-% of topical corticosteroid. In at leastone embodiment, the first composition includes 1.0 wt.-% of topicalcorticosteroid. In at least one embodiment, the inflammatory skindisease is selected from the group consisting of psoriasis, atopicdermatitis, eczema, forms of eczema, rash, and a combination of two ormore thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a method of treating inflammatory skin disease according tothe present disclosure;

FIG. 2 shows a method of treating inflammatory skin disease according tothe present disclosure; and

FIG. 3 shows a method of treating inflammatory skin disease according tothe present disclosure.

DETAILED DESCRIPTION

The present application discloses various formulations and methods forusing the same for the treatment of inflammatory skin diseases inmammals. According to one aspect of the present disclosure, aformulation for the treatment of psoriasis, atopic dermatitis, and otherforms of eczema, rash, and other inflammatory skin diseases isdisclosed. For the purposes of promoting an understanding of theprinciples of the present disclosure, reference will now be made tovarious embodiments and specific language will be used to describe thesame. It will nevertheless be understood that no limitation of the scopeof this disclosure is thereby intended, such alterations, modifications,and further applications of the principles of the disclosure beingcontemplated as would normally occur to one skilled in the art to whichthe disclosure relates.

A number of explanations and clinical trials are provided by way ofexplanation and not limitation. No theory of how the disclosure operatesis to be considered limiting, whether proffered by virtue ofdescription, comparison, or example. For the purposes of thisdisclosure, the term “emu oil” refers to lipid compositions, oils, andpreparations of oils derived from the emu.

Emu oil, extracted or rendered from the body fat of the emu bird, has anumber of beneficial properties for the treatment of inflammatory skindiseases. The beneficial properties of emu oil include that emu oil isnoncomedogenic, antibacterial, moisturizing, anti-inflammatory,emulsifying, enhances transdermal penetration, and has a low potentialfor skin irritation. Taking each of these beneficial properties in turn,emu oil is noncomedogenic, meaning emu oil will not clog skin pores.Other oils tend to clog pores in skin, which can result in thedevelopment of acne. Such other oils include synthetic oils, likemineral oils, or animal oils, like mink or lard. Moreover, emu oil hasbeen demonstrated to be antibacterial and moisturizing to skin.Bacterial secondary colonization and infection play important roles inthe pathogenesis of atopic dermatitis, and the antibacterial propertiesof emu oil address this contributing factor. Further, moisturizers bythemselves are therapeutic agents in the treatment of patients withpsoriasis, atopic dermatitis, and other forms of eczema becausemoisturizers can improve skin hydration and normalize keratinocytedifferentiation.

Emu oil has excellent skin barrier penetrating features and can enhancethe transdermal penetration of active compounds, compounds otherwiseunable to effectively treat disease beyond the epidermis. Emu oil isknown to contain triglyceride esters of long-chain saturated andunsaturated fatty acids, including oleic acid, linoleic acid, palmiticacid, and stearic acid. Table 1 contains the typical chemicalcomposition of emu oil which, being almost entirely triglyceride innature, is a nearly completely neutral lipid. The transdermalpenetration properties of emu oil are generally attributable to oleicacid, which enables penetration by fluidizing the intercellular lipidsof the stratum corneum. However, studies of various long-chain fattyacids, including oleic acid, used as penetration enhancers have notreported a synergistic effect of using this particular property of emuoil with other active compounds as described herein.

Two other valuable properties of emu oil for a topical treatmentdelivery system are its emulsifying properties and low potential forirritation. Such emulsifying properties, absent the potential forirritation, enable emu oil to serve as both a carrier and an activecompound in a formulation. In addition to the beneficial propertiesmentioned above, emu oil has anti-inflammatory properties. For example,topically administered emu oil has been shown to be as effective asorally administered, high-dose ibuprofen. Research suggests that atleast some of emu oil's anti-inflammatory properties are due toTNF-alpha inhibition, which is a key target inflammatory molecule insystemic psoriasis therapy. Examples of prescription treatments forsystemic psoriasis that operate by inhibiting TNF-alpha include Enbrel®and Humira®. However, prior to the present disclosure, no topicalformulation with TNF-alpha inhibitory effects has been used to treatinflammatory or any other disease of the skin. Therefore, emu oil mayact as a therapeutic agent for some skin diseases independent of anyother active compound.

Certain of the beneficial properties of emu oil are most effective intreating specific types of skin diseases and less effective on others.Nonetheless, by combining emu oil with additional active compounds, thebeneficial properties of emu oil may potentiate the therapeutic effectsof both the emu oil and the additional active compounds. Accordingly, inat least one embodiment of the present disclosure, emu oil may beincluded in a formulation to dissolve one or more additional activecompounds, carry the one or more additional active compounds through theskin barrier, and provide one or more therapeutic effects that aresynergistically enhanced by the combination with the one or moreadditional active compounds.

In at least one embodiment according to the present disclosure, emu oilmay be combined with a non-sedating antihistamine compound to treatinflammatory skin diseases such as psoriasis and atopic dermatitis. Onenon-limiting example of a non-sedating antihistamine is cetirizine.Cetirizine is commonly used orally to treat hay fever, urticaria (i.e.,hives), angioedema, and allergies. In addition to antiallergic,bronchodiliatory, and antispasmodic properties, cetirizine has numerouspharmacological effects that are highly useful for the treatment ofinflammatory skin disease if used as a topical agent.

As a potent second-generation antihistamine, cetirizine has antipruriticproperties that are very beneficial in treating inflammatory skinconditions, particularly atopic dermatitis, which has been described asa vicious cycle of itch-scratch-itch. In addition to relieving thesymptoms of itch, antipruritic antihistamines help to preventprogression of the disease by suppressing the scratching impulse (i.e.,the so-called Koebner phenomenon). Moreover, as a second-generation,non-sedating antihistamine, cetirizine has an excellent safety profile,which enables cetirizine (marketed as Zyrtec®) to be soldover-the-counter without a prescription. Further, cetirizine and itsrelated isomers are unique among non-sedating antihistamines in thateach has various anti-inflammatory properties useful for the treatmentof inflammatory skin disease. Namely, cetirizine inhibits expression ofadhesion molecules in patients with both atopic dermatitis and psoriasisand inhibits both T lymphocytes and monocytes, which play a central rolein the pathogenesis of atopic dermatitis and psoriasis. Finally,cetirizine exerts anti-inflammatory effects on neutrophils apart from H₁antagonism and inhibits eosinophil-related skin inflammation.

The anti-inflammatory properties of cetirizine are distinct from itsother H₁ antihistamine features. For example, diphenhydramine (marketedas Benadryl®) is specifically contraindicated to treat inflammatory skindisease, such as eczema and psoriasis. In fact, where sold in the UnitedStates, the packaging for diphenhydramine includes a warning labelclearly stating that it should not be used on “raw or broken skin” or“areas producing discharge.” Other commonly used non-sedatingantihistamines that do not have anti-inflammatory properties includeloratadine (marketed as Claritin®) and fexofenadine (marketed asAllegra®). Therefore, not all non-sedating, H₁ antihistamines areappropriate for the treatment of inflammatory skin diseases.

Though emu oil and cetirizine both have anti-inflammatory properties,each utilizes completely different biochemical pathways. Consequently,instead of enabling merely additive beneficial anti-inflammatoryeffects, the combination of emu oil and cetirizine provides asynergistic enhancement of the beneficial effects of both activecompounds in treating inflammatory skin conditions. Furthermore, emuoil, in addition to being a therapeutic agent, also enables penetrationof cetirizine into the skin, thereby improving the efficacy ofcetirizine separate from the synergistic effect.

Cetirizine is a racemic 50/50 mixture of levocetirizine, which is theactive enantiomer (or L-stereoisomer), and the much less biologicallyactive enantiomer (or D-stereoisomer). Like cetirizine, levocetirizineis a non-sedating antihistamine that includes anti-inflammatoryproperties. Accordingly, in at least one embodiment of the presentdisclosure, emu oil may be combined with levocetirizine to treatinflammatory skin diseases such as psoriasis and atopic dermatitis.Other non-sedating, anti-inflammatory antihistamines include, but arenot limited to rupatadine, acrivastine, ebastine and bilastine.

In at least one embodiment of the present disclosure, emu oil may becombined with a topical steroid compound, such as a glucocorticoid, totreat inflammatory skin diseases such as psoriasis and atopicdermatitis. Non-limiting examples of topical glucocorticoids includedesoximetasone, fluocinonide, halcinonide, amcinonide, andhydrocortisone. Such topical glucocorticoids have anti-inflammatoryproperties by preventing phospholipid release, decreasing eosinophilaction, and a number of other mechanisms. Accordingly, theanti-inflammatory properties of topical glucocorticoids operate bycompletely different biochemical pathways than either H.sub.1antihistamines or emu oil.

Topical steroids are among the most commonly prescribed topicalmedications for the treatment of rash, eczema, and dermatitis. However,the use of topical steroids comes with a risk of various side effects,including allergic contact dermatitis, steroid-induced dermal atrophy,and tachyphylaxis, among others. Steroid-induced dermal atrophy is aparticularly common side effect because glucocorticoids are absorbed atdifferent rates depending on the thickness of the stratum corneum.Consequently, a mild topical steroid that works on the face may achievelittle on the palm, but a potent steroid required to treat the thickskin of the palm may quickly cause side effects on the face. As aresult, weaker topical steroids generally are utilized for thin-skinnedand sensitive areas, especially areas under occlusion, such as thearmpit and groin. However, moderate steroids are commonly used foratopic dermatitis and eczema, among others, and strong steroids are usedfor such conditions as psoriasis, lichen sclerosis, discoid lupus,nummular eczema, and severe atopic dermatitis in adults. When theseconditions appear in thin-skinned and sensitive areas, the risk ofsteroid-induced dermal atrophy is increased.

The formulations of the present disclosure enable the use of relativelyweaker topical steroids or, alternatively, less frequent use of strongertopical steroids for the treatment of inflammatory skin diseases. In oneisolated clinical study performed in connection with the presentdisclosure, a middle-aged patient with severe lichen sclerosis (“LSA”)of the genitals was first given a standard 4-week treatment with anultra-potent topical glucocorticoid. Though the condition of the LSAgreatly improved, the patient developed severe side effects associatedwith topical steroid therapy, namely, persistent yeast dischargeinfections and dermal atrophy of the skin. The application of thetopical glucocorticoid was decreased to an as-needed basis, whichamounted to at least twice a week. However, even at the decreased rateof application, the patient continued to suffer discharge infections andthe skin continued to thin due to the dermal atrophy.

In response, and in accordance with the present disclosure, the therapywas again revised to include the application of emu oil twice a day andtopical glucocorticoid on an as-needed basis only. In the following twomonths, the patient reported that the discharge infections had resolved,as had the symptoms of pain and itching, and the dermal atrophy hadended and reversed. Further, the patient also reported using the topicalglucocorticoid only once in the preceding two months. Consequently, thecombination of treatments using emu oil and a topical steroid produced asignificant and unexpectedly superior outcome to the use of ultra-potenttopical glucocorticoid alone. Without being bound to a particulartheory, the inventor suggests that the antibacterial, anti-inflammatory,and moisturizing properties of the emu oil were effective in treatingthe discharge infection and side effects of the topical steroid, whilethe transdermal penetration properties of emu oil synergisticallypotentiated the beneficial effects of the topical steroid, therebyenabling its less frequent but more effective use.

In at least one embodiment according to the present disclosure, a firstformulation 10 may contain by weight 75-100% emu oil, 0.1-5.0%non-sedating antihistamine, and 0.1-1.0% preservative, with the balancebeing a neutral emulsifying solvent. In at least one embodiment, thefirst formulation 10 may contain by weight 75-100% emu oil, 0.1-5.0%cetirizine, 0.1-1.0% methylparaben preservative, and the balancepropylene glycol or other neutral emulsifying solvent. In at least oneembodiment, the first formulation 10 may contain by weight at least 85%emu oil, 2.0% cetirizine, 0.2% methylparaben preservative, and thebalance propylene glycol. In at least one embodiment, the firstformulation 10 may contain by weight 75-100% emu oil, 0.1-5.0%levocetirizine, 0.1-1.0% methylparaben preservative, and the balancepropylene glycol or other neutral emulsifying solvent. In at least oneembodiment, the first formulation 10 may contain by weight at least 85%emu oil, 2.0% levocetirizine, 0.2% methylparaben preservative, and thebalance propylene glycol.

In at least one embodiment according to the present disclosure, a secondformulation 20 may contain by weight 75-100% emu oil, 0.1-5.0%non-sedating antihistamine, 0.1-3.0% topical steroid, and 0.1-1.0%preservative, with the balance being a neutral emulsifying solvent. Inat least one embodiment, the second formulation 20 may contain by weight75-100% emu oil, 0.1-5.0% cetirizine, 0.1-1.0% desoximetasone, 0.1-1.0%methylparaben preservative, and the balance propylene glycol or otherneutral emulsifying solvent. In at least one embodiment, the secondformulation 20 may contain by weight at least 85% emu oil, 2.0%cetirizine, 0.25% desoximetasone, 0.2% methylparaben preservative, andthe balance propylene glycol. In at least one embodiment, the secondformulation 20 may contain by weight 75-100% emu oil, 0.1-5.0%cetirizine, 0.1-2.0% hydrocortisone, 0.1-1.0% methylparabenpreservative, and the balance propylene glycol or other neutralemulsifying solvent. In at least one embodiment, the second formulation20 may contain by weight at least 85% emu oil, 2.0% cetirizine, 1.0%hydrocortisone, 0.2% methylparaben preservative, and the balancepropylene glycol.

In at least one embodiment according to the present disclosure, thesecond formulation 20 may contain by weight 75-100% emu oil, 0.1-5.0%levocetirizine, 0.1-1.0% desoximetasone, 0.1-1.0% methylparabenpreservative, and the balance propylene glycol or other neutralemulsifying solvent. In at least one embodiment, the second formulation20 may contain by weight at least 85% emu oil, 2.0% levocetirizine,0.25% desoximetasone, 0.2% methylparaben preservative, and the balancepropylene glycol. In at least one embodiment, the second formulation 20may contain by weight 75-100% emu oil, 0.1-5.0% levocetirizine, 0.1-2.0%hydrocortisone, 0.1-1.0% methylparaben preservative, and the balancepropylene glycol or other neutral emulsifying solvent. In at least oneembodiment, the second formulation 20 may contain by weight at least 85%emu oil, 2.0% levocetirizine, 1.0% hydrocortisone, 0.2% methylparabenpreservative, and the balance propylene glycol.

In one aspect of the present disclosure, the formulations disclosedherein may be used in a method 100 of treating inflammatory skindiseases such as atopic dermatitis, rash, and psoriasis as shown inFIG. 1. The method 100 may include a step 110 of applying the firstformulation 10 to an affected area of skin. The method 100 may furtherinclude a step 120 of periodically repeating application of the firstformulation 10 to the affected area of skin until the disease isresolved or controlled. Alternatively, a method 200 for treatinginflammatory skin diseases such as atopic dermatitis, rash, andpsoriasis is shown in FIG. 2. The method 200 may include a step 210 ofapplying the second formulation 20 to an affected area of skin. Themethod 200 may further include a step 220 of periodically repeatingapplication of the second formulation 20 to the affected area of skinuntil the disease is resolved or controlled.

In one embodiment according to the present disclosure, a kit 50 mayinclude a package, such as a tube, vial, dispenser, or other suitablecontainer, of the first formulation 10 and a separate package of thesecond formulation 20. The kit 50 may be used with the methods describedherein for the staged or pulsed treatment of inflammatory skin disease.The kit 50 enables a physician to direct a patient to use the secondformulation 20, including the combination of emu oil, non-sedatingantihistamine, and topical steroid, for a relatively short period oftime and for localized areas to clear active inflammatory lesions andthen to use the first formulation 10, including the combination of emuoil and non-sedating antihistamine, as a moisturizer to preventrecurrence of the disease, thereby treating the disease while avoidingthe side effects of chronic topical steroid use described herein.

In one aspect of the present disclosure, one or more of the formulationsdisclosed herein, such as in the kit 50, may be used in a method 300 fortreating inflammatory skin diseases as shown in FIG. 3. The method 300may include a step 310 of periodically applying the second formulation20 to an affected area of skin for a relatively short period of time.The period of time may be limited by a given patient's tolerance for thespecific composition of the second formulation 20, by the sensitivity ofthe area of the patient's skin under treatment, or by resolution of theskin condition. The method 300 may further include a step 320 ofperiodically applying the first formulation 10 to an affected area ofskin to avoid the side effects of chronic topical steroid use describedherein and to prevent recurrence of the disease. Optionally, the method300 may include a step 330 of repeating the periodic application of thesecond formulation 20 to the affected area as required to maintaincontrol of chronic disease. For example, the method 300 may include theapplication of the second formulation 20 (step 310) for two or threeconsecutive days, followed by the application of the first formulation10 (step 320), and repeating (step 330) as needed to maintain control ofa particular disease. Such alternating methods of therapy are commonlyknown as “pulse therapy.”

The efficacy of combining emu oil with non-sedating antihistamine andwith topical steroid was determined by the following experiment. Thefollowing experiment is illustrative, but not limiting, of the methodsand compositions of the present disclosure. Other suitable modificationsand adaptations of the variety of conditions and parameters normallyencountered in clinical therapy and obvious to those skilled in the art,having the benefit of this disclosure, are within the scope of thepresent disclosure.

Experiment

In order to determine the efficacy of combining emu oil, a non-sedatingantihistamine, and a topical steroid as active compounds for thetreatment of inflammatory skin disease, a clinical study was conducted.The study was designed to determine: (i) the efficacy of the activecompounds in treating inflammatory skin disease; (ii) whether the activecompounds worked synergistically or simply provided additive effects;and (iii) the relative quantifiable effectiveness of the activecompounds. As a single blind study, ten research subjects received fourtubes of preparations in cream form, labeled as A, B, C, and D, withoutknowledge of the formulations therein. However, a principal investigatorand a study coordinator knew and recorded the formulations contained ineach tube. Regarding the active compounds included in the study, Cream Aincluded desoximetasone and cetirizine in an emu oil base, Cream Bincluded desoximetasone in a propylene glycol base, Cream C includeddesoximetasone in an emu oil base, and Cream D included desoximetasoneand cetirizine in a propylene glycol base. Each cream included anidentical amount of desoximetasone, namely 0.25% by weight. Further,each cream included methylparaben as a preservative and varying amountsof propylene glycol as a neutral emulsifying solvent. Cream B, whichincluded only desoximetasone as an active compound, was used as acontrol to provide a reference point for the degree of improvementobserved for the other trial preparations. The study was conducted for15 days.

To improve the statistical significance of the results, the study wasdesigned as a comparative half/split body study. Specifically, eachresearch subject applied each of the trial creams to diseased skin ondifferent locations on the subject's body. For example, a given subjectapplied Cream A to one side of the body and, on the identical abnormalskin condition on the opposite side of the body, applied cream B, C, orD. Consequently, each research subject was his/her own positive andnegative control. At the end of the study, each research subjectcompleted a questionnaire specifically asking “which of the four creamsworked the best” and asking the subject to numerically rate the efficacyof each cream on a scale of 1 (not effective) to 10 (extremelyeffective). The subjects' ratings were then multiplied by a factor often to enable simple percentage point comparisons between the trialcreams. Moreover, each subject was asked to report any systemic ordermatological side effects of the creams, such as irritation, stinging,or pruritus.

The clinical response of each subject was assessed by the principalinvestigator, a physician trained, experienced, and Board Certified indermatology, at the end of the 15-day clinical study by comparing thecondition of the subjects to a pre-trial evaluation on the same 1 to 10scale used by the subjects. Similarly, the physician's evaluations werethen multiplied by a factor of ten to enable simple percentage pointcomparisons between the trial creams. Finally, the study coordinatorobtained clinical photographs of all areas treated at the beginning andend of the study.

The research subjects did not use any other prescription medication orover-the-counter topical preparation during the duration of the study.Informed written consent was obtained prior to initiation of the studyfrom each research subject. No financial compensation was provided toany of the research subjects; however, each received a complimentaryoffice visit and free medication. Further, at the end of the study, thesubjects were offered and received a free complimentary tube of thecream of their choice (either cream A, B, C, or D). The subjects'clinical diagnoses included either psoriasis, atopic dermatitis, orstasis dermatitis.

Table 2 presents the physician's evaluations of the improvement orworsening of the research subjects' skin conditions by the end of thestudy, relative to the beginning of the study, for each of the trialcreams A, B, C, and D. As shown Table 2, Cream A was rated mosteffective because it demonstrated the greatest improvement compared tocreams B, C, and D, as reflected in the mean evaluation ratings acrossall subjects. Further, statistical analysis determined that thedemonstrated improved effect of Cream A was statistically significant(i.e., p<0.05). Table 2 further shows that Cream A was demonstrated tobe 63% more effective than Cream B (i.e., the control) to astatistically significant degree as evaluated by the physician.

Table 2 includes a column of data for the “Additive Effect of Creams Cand D” calculated for each subject based upon the physician'sevaluations. The calculated additive effect of Cream C and Cream D wasdetermined by, first, subtracting the rated effect of Cream B (thecontrol) from the ratings given to Cream C and Cream D, which results ina value representing the beneficial effect of each cream in addition tothe effect provided by Cream B. The resulting additional effects werethen added together. Essentially, the calculated additive effectquantifies the combined effects of Cream C and Cream D, beyond theeffect of the control cream, attributable to the active compoundsoperating separately. Thus, the calculated additive effect representsthe expected or anticipated effect of combining and administering thethree active compounds, desoximetasone, cetirizine, and emu oil. On theother hand, the extent to which the rated effect of Cream A exceeds thecalculated additive effect of Cream C and Cream D represents theunexpected and synergistic effect of combining and administering thethree active compounds together. The synergistic effect may becalculated by subtracting the calculated additive effect of Cream C andCream D from the rated evaluations for Cream A. Accordingly, Table 2further includes the resulting unexpected and synergistic effect foreach subject under column heading, “Synergistic Effect of Cream A,”which contains the calculated percentage point improvement produced bythe synergistic effect of Cream A beyond the simple additive effects ofthe active compounds administered separately via Cream C and Cream D.

As shown in Table 2, Cream A was on average 31% more effective than thenet effects of Cream C and Cream D taken separately. Further, thesynergistic effect was statistically significant. Because the ratingsgiven to Cream A were statistically greater than the calculated additiveeffect of Cream C and Cream D, one may conclude that the combined effectof the active compounds included in Cream A exceeded the expected effectof these compounds acting separately by 31% on average. Therefore, thestudy unequivocally demonstrated that desoximetasone, cetirizine, andemu oil synergistically potentiate each other's beneficial effects andthat the synergistic effect is statistically significant. Furthermore,the study unequivocally demonstrated that cetirizine and emu oilsynergistically potentiate each other's beneficial effects and that thesynergistic effect is statistically significant.

Table 3 presents the research subjects' ratings of their own skinconditions at the end of the study, relative to the beginning of thestudy, for each of the trial creams A, B, C, and D. As shown in Table 3,the subjects' ratings generally corroborated the physician'sevaluations. For example, each of the research subjects rated Cream A asthe most effective for the treatment of his/her skin disease to astatistically significant degree. As shown in Table 3, Cream A wasdemonstrated to be 58% more effective than Cream B (the control) to astatistically significant degree as rated by the research subjects. Inaddition, Cream A was on average 28% more effective than the net effectsof Cream C and Cream D taken separately, thereby demonstrating thesynergistic effect of combining desoximetasone, cetirizine, and emu oilas indicated by the subjects' ratings. Further, each research subject,at the end of the study, requested an additional free tube of Cream Aonly.

Certain individual results were particularly dramatic. For example,Subject #2, with chronic atopic dermatitis on the neck unresponsive toultra-potent clobetasol steroid cream, had complete clearance of therash after a 5-day therapy with Cream A. Subject #5, with chronic severeplaque psoriasis under reasonable control with subcutaneous etanerceptinjections, had persistent psoriatic lesions on the abdomen unresponsiveto therapy with potent fluocinonide steroid cream. However, the diseasehad completely cleared within 15 days of therapy with Cream A.

None of the research subjects reported any systemic side effects fromany of the creams A, B, C, or D. Concerning cutaneous dermatologicalside effects, one subject reported mild pruritus associated with Cream Ause. Nonetheless, that subject still gave Cream A the highest ranking inall categories and requested an additional tube of Cream A. None ofother research subjects reported dermatological side effects associatedwith the use of Cream A.

The clinical study clearly demonstrated that the combination of anon-sedating antihistamine, a topical steroid, and emu oilsynergistically potentiates the mutually beneficial effects of theactive compounds in treating skin inflammatory conditions, utilizingdifferent biochemical pathways. Further, the study clearly demonstratedthat the combination of a non-sedating antihistamine and emu oilsynergistically potentiates the mutually beneficial effects of theactive compounds in treating skin inflammatory conditions, utilizingdifferent biochemical pathways.

While various embodiments of a formulation for the treatment ofinflammatory skin diseases and methods for using the same have beendescribed in considerable detail herein, the embodiments are merelyoffered by way of non-limiting examples of the disclosure describedherein. It will therefore be understood that various changes andmodifications may be made, and equivalents may be substituted forelements thereof, without departing from the scope of the disclosure.Indeed, this disclosure is not intended to be exhaustive or to limit thescope of the disclosure.

Further, in describing representative embodiments, the disclosure mayhave presented a method and/or process as a particular sequence ofsteps. However, to the extent that the method or process does not relyon the particular order of steps set forth herein, the method or processshould not be limited to the particular sequence of steps described.Other sequences of steps may be possible and are therefore contemplatedby the inventor. Therefore, the particular order of the steps disclosedherein should not be construed as limitations of the present disclosure.In addition, disclosure directed to a method and/or process should notbe limited to the performance of their steps in the order written. Suchsequences may be varied and still remain within the scope of the presentdisclosure.

TABLE 1 Typical Emu Oil Fatty Acid Composition Fatty Acid Percentage byWeight Myristic 0.4% Palmitic 21.5% Palmitoleic 3.7% Stearic 10.6% Oleic51.4% Linoleic 12.7% Linolenic 0.9%

TABLE 2 Physician Evaluations of Trial Creams Additive Cream ASynergistic Effect Improvement Effect of Cream B of Creams over ControlCream A Subject Cream A (Control) Cream C Cream D C & D (%) (%) 1 100 4050 60 30 60 30 2 90 50 70 60 30 40 10 3 90 30 50 40 30 60 30 4 80 50 6060 20 30 10 5 100 50 60 70 30 50 20 6 100 30 40 50 40 70 30 7 70 −50 −400 60 120 60 8 100 20 30 30 40 80 40 9 100 60 60 70 10 40 30 10  100 2030 40 30 80 50 Mean 93 30 41 48 32 63 31

TABLE 3 Patient Ratings of Trial Creams Additive Cream A SynergisticEffect Improvement Effect of Cream B of Creams over Control Cream ASubject Cream A (Control) Cream C Cream D C & D (%) (%) 1 100 30 50 5040 70 30 2 80 50 50 70 20 30 10 3 100 50 80 50 30 50 20 4 70 20 50 30 4050 10 5 100 70 90 50 0 30 30 6 100 20 50 70 80 80 0 7 100 0 0 0 0 100100 8 100 50 50 80 30 50 20 9 90 40 50 50 20 50 30 10  100 30 40 70 5070 20 Mean 94 36 51 52 31 58 27

The invention claimed is:
 1. A topical composition for treating skininflammation, the composition comprising: 2.0% wt.-% of cetirizine;0.25% wt.-% of desoximetasone; at least 85% wt.-% of emu oil; 0.2% wt. %methylparaben; and the balance of propylene glycol.